Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrate derivatives have in vivo and in vitro platelet anti-aggregant properties in addition to their vasodilatory effects. The mode of action is related to increased intracytoplasmic cyclic GMP concentrations. It has been shown that isosorbide dinitrate (ISDN) has this type of platelet anti-aggregant activity but the reported results about the active concentrations and the inhibited pathways of activation are contradictory. This study was designed to determine whether ISDN has in vitro platelet anti-aggregant activity at low doses and to verify if this effect is selective by aggregation induced by ADP. Finally, a possible potentialisation of the inhibitors due to ISDN was looked for with cyclic nucleotide phosphodiesterase inhibitors and with agents simulating the effect of adenylate cyclase. The results showed that: 1) ISDN had platelet anti-aggregant activity in vitro at concentrations of about 10-7 M, 2) that this effect was not limited to the aggregation induced by ADP as the aggregation induced by PAF-acether was also inhibited by low dose ISDN, 3) of the cyclic nucleotide modulators tested, only quercetine (flavonoide) potentialised the effects of ISDN.
Arch Mal Coeur Vaiss 1992 Apr
PMID:[Isosorbide dinitrate inhibits in vitro platelet aggregation at submicromolar concentrations]. 132 33

The effects of sinoaortic denervation (SAD) on the development of left ventricular hypertrophy (R: heart weight/total body weight; LVT : left ventricular thickness), myocardial beta-adrenergic receptivity ([125I]CYP binding; adenylate cyclase activity) and plasma catecholamine levels (HPLC) were investigated in both normotensive (group 1) and hypertensive dogs evaluated (group 2) 1 and 18 months (group 3) after SAD. Noradrenaline (NA) and adrenaline (A) plasma levels were 461 +/- 54 and 85 +/- 45 pg/ml in controls, 861 +/- 185 and 191 +/- 23 pg/ml in group 2 (P < 0.05) and were normal in group 3 (426 +/- 132 and 110 +/- 16 pg/ml). R and LVT values were higher (p < 0.05) in SAD dogs (R = 7.7 +/- 0.1 and 7.8 +/- 0.2; LVT = 13.6 +/- 1.3 and 14.2 +/- 0.9 mm in groups 2 and 3 respectively) than in group 1 (R = 6.7 +/- 0.1, LVT = 9.3 +/- 0.8 mm). In group 1, the total number of beta-adrenoceptors (beta-AR) was 37 +/- 11 and 29 +/- 6 fmol/mg prot in left ventricule (LV) and right auricle (RA) respectively. Bmax was significantly lower in group 2 (LV: 10 +/- 3; RA: 13 +/- 2 fmol/mg prot, p < 0.05) than in group 1 but was normal in group 3 (LV: 37 +/- 3 and RA: 31 +/- 3 fmol/mg prot).(ABSTRACT TRUNCATED AT 250 WORDS)
Arch Mal Coeur Vaiss 1992 Aug
PMID:[Beta adrenergic receptors and experimental left ventricular hypertrophy]. 133 53

Calmodulin is a small protein (16.7 KDa) calcium receptor which plays a fundamental part in vasomotricity. When intracellular Ca2+ concentrations increase (from 0.1 to 10 M), calmodulin fixes four Ca2+, changes its conformation and interacts with its target proteins. In vascular smooth muscle it activates the kinase of the myosine light chain and interacts with caldesmone to allow phosphorylation of myosine and the actine-myosine interaction. These two processes lead to vascular smooth muscle contraction. Calmodulin also activates enzymes involved in the regulation of the cyclic nucleotides: adenylate cyclase which synthesises cyclic AMP and the calmodulin dependent phophodiesterase which preferentially hydrollyses cyclic GMP. Cyclic AMP and GMP contribute to the relaxation of smooth muscle by inhibiting, the kinase of the myosine light chain and stimulating the Ca2+ ATPase responsible for the extrusion of Ca2+. The contractile action of calmodulin is counterbalanced by the relaxing effects of cyclic AMP and GMP. In addition, caldomodulin participates in the control of vasomotricity by regulating the phosphorylation and dephosphorylation of proteins influencing intracellular Ca2+ concentrations and the activation of contractile proteins. Caldomodulin activates the enzyme responsible for the synthesis of nitric oxide in the endothelium (endothelium derived relaxing factor) and thereby participates in the endothelium dependent relaxation process.
Arch Mal Coeur Vaiss 1991 Jan
PMID:[Calcium-calmodulin and vasomotor activity]. 205 31

A hyperreactivity to thrombin of platelets from spontaneously hypertensive rats (SHR) has been shown in vitro but no signs of platelet hyperactivation has been evidenced in vivo in these animals. Therefore, we have studied the effect of two inhibitory agents, PGE1 and magnesium, on platelet activation. The first drug is known to specifically act through adenylate cyclase stimulation, the second to have diffuse cellular effects as enzymatic cofactor. Blood of SHR and WKY adult animals was drawned by carotid catheterism. After isolation, platelets were loaded with 5-HT (either tritiated or not), then washed and incubated in a Hepes buffer, pH 7.4 with various concentrations of external calcium and magnesium, at 30 degrees C and with minimal stirring. Thrombin-induced platelet 5-HT secretion was evaluated, after preincubation in the presence of tritiated serotonin, in percentage of the initial load. Cyclic AMP content was measured by radioimmunoassay. Calcium influx was measured 30 seconds after thrombin addition by 45Ca incorporation. The inhibitory effect of PGE1 on 5-HT secretion is more important with SHR platelets than WKY ones, at 5 X 10(-8) and 10(-7)M. On the other hand, SHR platelets are less sensitive to inhibitory effect of external magnesium (1 to 10 mM). Between 10(-7) and 10(-6)M, PGE1 induces an increase of cAMP content, significantly more important in SHR, which persists in the presence of isobutylmethylxanthine (IBMX) 10(-5)M. Platelet reaction to thrombin is the more decreased as intracellular cAMP level before thrombin addition is enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)
Arch Mal Coeur Vaiss 1987 Jun
PMID:[Changes in the inhibitory processes of platelet activation in the SHR rat]. 282 48

The hormone-sensitive adenylate cyclase system of plasma membrane is composed of at least three types of proteins: hormone receptors, activatory (Gs) and inhibitory (Gi) guanine nucleotide-regulatory proteins and the catalytic unit (C). Abnormal hormonal regulations of platelet adenylate cyclase in both humans and experimental animals have been reported to occur in hypertension. However, little is known about the mechanisms for these alterations. The aim of the present study was to compare the activity of C and the inhibitory capacity of Gi in platelet membranes from spontaneously hypertensive rats (SHR) and their normotensive controls (WKY). Adenylate cyclase activity of 40,000 g membranes was assessed at pH 7.5 with 0.1 mM (alpha-32P) ATP and an appropriate bivalent cation (Mn2+ or Mg2+). Under incubation conditions that uncoupled C from Gs and Gi (25 mM MnCL2, 100 microM forskolin), a significantly lower adenylate cyclase activity was measured in membranes from SHR rats (2.07 +/- 0.12 vs 2.36 +/- 0.1 nmol cAMP/mn/mg of protein, p less than 0.05). This difference between the two strains was also observed in platelet homogenates. In a second kind of experiments, membranes were incubated with 2.1 mM MgCl2 instead of MnCl2. In both strains of rats, low concentrations of Gpp (NH)p (10 to 300 nM) inhibited adenylate cyclase activity when stimulated by 50 microM forskolin. However, the maximal extent of inhibition was significantly reduced in hypertensive rats (49.7 +/- 2.4 vs 60.5 +/- 2.3 p. 100, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Arch Mal Coeur Vaiss 1988 Jun
PMID:[Anomalies of the adenylate cyclase system in platelets of the SHR rat]. 284 72

The effect of left ventricular chronic pressure overload on right atrial (RA) and left ventricular (LV) myocardial beta-adrenoceptor (beta-AR) density and subtypes ([I125] cyanopindolol binding), adenylate cyclase activity (AC) and ADP-pertussis toxin ribosylated proteins was investigated in 13 patients with aortic stenosis (AO) and compared with the results obtained in 10 patients with mitral stenosis (MI) taken as controls. None of the patients included had any impairement of systolic function or increased plasma catecholamine levels. The total number of beta-AR in RA (62 +/- 6 vs 77 +/- 12 fmoles/mg prot) and LV (39 +/- 7 vs 32 +/- 2 fmoles/mg prot) was similar in AO and in MI. The percentage of beta 1-AR was significantly lower in LV from AO (35 +/- 11 vs 73 +/- 5% in MI) but identical in RA (79 +/- 5 vs 73 +/- 8%). The basal activity of AC was similar in membranes from patients with AO (19 +/- 4 and 22 +/- 5 pmol.mg-1 prot in RA and LV) and in controls (21 +/- 6 and 27 +/- 3 pmol.mg-1 prot in RA and LV). Isoprenaline-induced stimulation of AC was significantly lower in LV membranes from patients with AO (7 +/- 6 vs 45 +/- 6% in MI) but remained identical in RA membranes (51 +/- 18 vs 36 +/- 18% in MI). The quantification of ADP-pertussis toxin ribosylated proteins indicated a lower substrate concentration in myocardial membranes from patients with AO when compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Arch Mal Coeur Vaiss 1993 Aug
PMID:[Beta-adrenergic receptivity and left ventricular hypertrophy caused by pressure overload in man]. 812 8